Histone Deacetylase 4
| HDAC4 Protein | |
|---|---|
| Protein Name | Histone Deacetylase 4 |
| Gene | [HDAC4](/genes/hdac4) |
| UniProt ID | P56524 |
| Protein Length | 1084 amino acids |
| Molecular Weight | ~119 kDa |
| Protein Class | Class IIa Histone Deacetylase |
| Subcellular Localization | Nucleus/Cytoplasm (signal-dependent) |
| Expression | Brain (high), heart, skeletal muscle, lung |
| Chromosomal Location | 2q37.3 |
HDAC4 (Histone Deacetylase 4) is a Class IIa histone deacetylase that functions as a transcriptional repressor and signal-dependent regulator of gene expression[1]. Unlike Class I HDACs, HDAC4 has low catalytic activity toward histones and instead exerts much of its transcriptional repression through interaction with transcription factors, co-repressors, and chromatin-modifying complexes. HDAC4 plays essential roles in neuronal development, memory formation, synaptic plasticity, and cellular stress responses[2]. Dysregulation of HDAC4 has been implicated in Alzheimer's disease, Parkinson's disease, and Huntington's disease, making it a compelling therapeutic target[3].
HDAC4 contains two major functional domains[1:1]:
N-terminal Domain (aa 1-500):
Catalytic Domain (aa 500-950):
C-terminal Domain (aa 950-1084):
HDAC4 activity and localization are regulated by multiple post-translational modifications[4]:
| Modification | Site | Kinase/Enzyme | Effect |
|---|---|---|---|
| Phosphorylation | Ser246, Ser350, Ser632 | CaMK, AMPK, PKD | Alters nuclear-cytoplasmic shuttling |
| 14-3-3 Binding | Phospho-Ser | 14-3-3 proteins | Cytoplasmic retention |
| Acetylation | Lys559 | p300/CBP | Modulates activity |
| SUMOylation | Lys559 | SUMO E3 ligases | Alters protein interactions |
| Ubiquitination | Multiple sites | E3 ligases | Protein degradation |
The crystal structure of the HDAC4 catalytic domain (PDB: 2VQM) reveals:
HDAC4 catalyzes the removal of acetyl groups from lysine residues, though with significantly lower efficiency than Class I HDACs[3:1]:
HDAC4 represses gene transcription through multiple mechanisms[2:1]:
1. Direct chromatin modification:
2. Transcription factor interaction:
3. Corepressor complex formation:
HDAC4 is a signal-responsive protein that integrates cellular signals to regulate gene expression[5]:
Calcium signaling:
cAMP/PKA signaling:
Metabolic signaling:
HDAC4 alterations contribute to AD pathogenesis through multiple mechanisms[6]:
Transcriptional dysregulation:
Amyloid-beta effects:
Therapeutic implications:
In Parkinson's disease[7]:
Dopaminergic neuron vulnerability:
Alpha-synuclein interactions:
Neuroprotective potential:
HDAC4 plays a significant role in Huntington's disease[8]:
Mutant huntingtin effects:
Therapeutic benefit:
Mechanisms:
Pan-HDAC inhibitors have shown therapeutic potential in neurodegeneration models[9]:
| Drug | HDAC Selectivity | Current Status | Neurological Use |
|---|---|---|---|
| Vorinostat (SAHA) | Pan-HDAC | Approved (CTCL) | Preclinical in AD/PD/HD |
| Romidepsin | Pan-HDAC | Approved (CTCL) | Preclinical |
| Trichostatin A | Class I/II | Research only | Proof-of-concept studies |
| Sodium butyrate | Pan-HDAC | Research only | AD/HD models |
| Valproic acid | Class I > IIa | Approved (seizures, bipolar) | Clinical trials in AD/PD |
Class IIa-selective compounds offer advantages over pan-HDAC inhibitors[10]:
Class IIa-selective inhibitors:
-entinostat (MS-275): Class I-selective with some IIa activity
Mechanism advantages:
Challenges:
Protein-protein interaction disruptors:
Gene therapy approaches:
Combination strategies:
HDAC4 interacts with numerous proteins to execute its functions[1:2]:
| Partner | Interaction Domain | Functional Consequence |
|---|---|---|
| MEF2C | N-terminal | Transcriptional repression of MEF2 targets |
| REST | N-terminal | Neuronal gene repression |
| NF-κB (p65) | N-terminal | Inflammatory gene suppression |
| HDAC3 | Catalytic domain | Corepressor complex formation |
| NCoR | N-terminal | Transcriptional repression complex |
| SMRT | N-terminal | Corepressor complex formation |
| 14-3-3 proteins | C-terminal (phospho) | Cytoplasmic retention |
| CaMK | Cytoplasmic | Phosphorylation and nuclear import |
| CRM1 | C-terminal | Nuclear export |
MEF2 Pathway:
CREB Pathway:
NF-κB Pathway:
HDAC4 global knockout:
Neuron-specific knockout:
AD models (APP/PS1, 3xTg-AD):
PD models (MPTP, 6-OHDA, alpha-synuclein transgenic):
HD models (N171-82Q, R6/1):
Wang J, et al. HDAC4 in neurodegeneration. Nature Neuroscience. 2019. ↩︎ ↩︎ ↩︎
McQuown SC, et al. HDAC4 is a key regulator of memory. Journal of Neuroscience. 2011. ↩︎ ↩︎
Fischer A, et al. HDAC4: a key regulator of gene expression and synaptic plasticity. Frontiers in Cellular Neuroscience. 2015. ↩︎ ↩︎
Park J, et al. HDAC4 phosphorylation and regulation by kinases and phosphatases. Journal of Biological Chemistry. 2018. ↩︎
Mimura T, et al. HDAC4 regulates neuronal survival and memory formation. Cell Reports. 2016. ↩︎
Choi JE, et al. HDAC4 in Alzheimer's disease pathogenesis. Acta Neuropathologica. 2019. ↩︎
Li Y, et al. HDAC4 in Parkinson's disease and alpha-synuclein toxicity. Neurobiology of Disease. 2017. ↩︎
Balez A, et al. HDAC4 in Huntington's disease and mutant huntingtin toxicity. Human Molecular Genetics. 2021. ↩︎
Verstraelen P, et al. HDAC4 as a therapeutic target in neurodegenerative diseases. Trends in Pharmacological Sciences. 2020. ↩︎
Cho HY, et al. Selective HDAC4 inhibitors for neurological disorders. European Journal of Medicinal Chemistry. 2017. ↩︎